Many randomized clinical trials (RCTs) show acupuncture to be an effective treatment for diverse pain conditions. A closer look at this literature shows inconsistent findings: results lend to be confirmatory when RCTs compare acupuncture with not treatment or standard care controls; but inconclusive when RCTs compare genuine (verum) acupuncture with sham acupuncture suggesting that at least one healing component is mediated by something other than the acupuncture needles. A recent meta-analysis identified patient expectation of pain relief as the most robust predictor acupuncture treatment efficacy, regardless of verum or sham group assignment. Neuroimaging studies have begun identifying testable mechanistic hypotheses for both acupuncture and placebo analgesia. Our recent studies on healthy subjects demonstrate that in the context of positive expectation, both verum and sham acupuncture significantly relieve pain, however each functions via separable and distinct brain mechanisms. The current proposal will test whether these distinct brain activity patterns associated with pain relief following verum and sham acupuncture can be replicated in patients suffering from chronic knee pain due to osteoarthritis (OA). We propose two experiments in patients with knee OA that directly build upon recent research in our laboratory. In the first experiment we will systematically boost patients positive expectation for pain relief following verum or sham acupuncture, then quantify the relation between expectation, behavioral , and brain imaging (BOLD fMRI) measures of treatment response. In the second experiment, a similar boost of positive expectation for treatment will be compared to standard treatment and to waitlist control in a 6-week longitudinal mechanistic treatment study of verum acupuncture. fMRI BOLD data obtained before the first and after the 6th treatment sessions will be examined with respect to individual expectation of treatment outcome to identify potential treatment responses predictors. The significance of his innovative approach is that it could provide clear scientific evidence for how expectation modulates the impact of an analgesic treatment. The results of these experiments will advance our understanding of not only acupuncture and placebo analgesia mechanisms, but also help refine future research methods, and inform clinical practice.